Amyotrophic Lateral Sclerosis and Frontotemporal

Degeneration

ISSN: 2167-8421 (Print) 2167-9223 (Online) Journal homepage: http://www.tandfonline.com/loi/iafd20

Neuropsychological assessment in different King's

clinical stages of amyotrophic lateral sclerosis

Francesca Trojsi, Gabriella Santangelo, Giuseppina Caiazzo, Mattia Siciliano,

Teresa Ferrantino, Giovanni Piccirillo, Cinzia Femiano, Viviana Cristillo, Maria
Rosaria Monsurrò, Fabrizio Esposito & Gioacchino Tedeschi

To cite this article: Francesca Trojsi, Gabriella Santangelo, Giuseppina Caiazzo, Mattia Siciliano,
Teresa Ferrantino, Giovanni Piccirillo, Cinzia Femiano, Viviana Cristillo, Maria Rosaria Monsurrò,
Fabrizio Esposito & Gioacchino Tedeschi (2016): Neuropsychological assessment in different
King's clinical stages of amyotrophic lateral sclerosis, Amyotrophic Lateral Sclerosis and
Frontotemporal Degeneration, DOI: 10.3109/21678421.2016.1143513

To link to this article: http://dx.doi.org/10.3109/21678421.2016.1143513

View supplementary material Published online: 24 Feb 2016.

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 Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2016; 1–7

RESEARCH ARTICLE

Neuropsychological assessment in different King’s clinical stages of

amyotrophic lateral sclerosis

FRANCESCA TROJSI1, GABRIELLA SANTANGELO2, GIUSEPPINA CAIAZZO1,

MATTIA SICILIANO2, TERESA FERRANTINO1, GIOVANNI PICCIRILLO1,
CINZIA FEMIANO1, VIVIANA CRISTILLO1, MARIA ROSARIA MONSURRÒ1,
FABRIZIO ESPOSITO3 & GIOACCHINO TEDESCHI1
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1
Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples,
Naples, 2Department of Psychology, Second University of Naples, Caserta, and 3Department of Medicine and
Surgery, University of Salerno, Baronissi (Salerno), Italy

Abstract
Emerging evidence shows that cognitive deficits associated with frontal lobe dysfunction occur from early stages of
amyotrophic lateral sclerosis (ALS). We aimed to assess neuropsychological functioning at different stages of ALS to
further delineate the occurrence of cognitive impairment alongside the trajectory of ALS as defined by standard assessment
procedures. We investigated several cognitive domains in 74 ALS patients classified into four different clinical stages of
disease, according to a recently validated staging system for ALS (known as ‘King’s’ system), and evaluated and compared
the corresponding cognitive profiles. We found that data derived from global cognitive assessment and several executive
(i.e. Frontal Assessment Battery and Trail Making Test B-A) and long-term memory (i.e. memory prose) tests were
significantly different among the subsets of ALS patients, showing poorer performances with increasing clinical disability.
In conclusion, our preliminary results support the notion that mainly frontotemporal abilities may be impaired during the
ALS course and suggest that neuropsychological information could supplement the current clinical staging of patients.
However, ALS-specific multi-domain screening instruments, which allow to correct neuropsychological scores for physical
disability, should be validated in larger populations worldwide and routinely introduced in clinical practice.

Key words: Amyotrophic lateral sclerosis, cognitive impairment, clinical staging, neuropsychological assessment

Introduction small sample sizes and covered only some of the

It is now widely recognized that amyotrophic lateral
sclerosis (ALS), traditionally considered a pure
motor neuron disease, is a multi-system disorder
that exhibits extramotor dysfunctions, mainly in
cognitive domains, even at the early stages of disease
(1). In particular, approximately 5–15% of ALS
patients meet the diagnostic criteria for frontotem-
poral lobar degeneration (FTLD), predominantly
developing clinical features typical of the behav-
ioural variant frontotemporal dementia (bvFTD)
(2,3). Apart from the growing amount of neuropsy-
chological data from cross-sectional analyses (4–8),
results from longitudinal studies, albeit less numer-
ous, have principally identified language, executive
and behavioural dysfuncions during the ALS course
(9–12). However, these studies explored relatively
potentially dysfunctioning cognitive domains.
Therefore, the consolidation of these findings
would require larger sample sizes and the use of
ALS-specific tools for multi-domain cognitive
assessment to better characterize the association
between motor and cognitive impairments in ALS.
Of note, cognitive and behavioural screening instru-
ments are often not available or not validated in
languages other than the natives ones and, therefore,
most clinic- and population-based studies used
standard assessment procedures (6–10). With
these premises, we aimed to evaluate patterns of
cognitive and behavioural impairment in a clinic-
based sample of 74 ALS patients, classified in four
subsets according to the King’s clinical staging
system, that does not include cognitive informa-
tion (13). Albeit limited by the lack of a

Correspondence: G. Tedeschi, Second University of Naples, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Piazza
Miraglia 2, 80138 Naples, Italy, Fax: 39 0815665095. E-mail: gioacchino.tedeschi@unina2.it

(Received 7 July 2015; revised 14 December 2015; accepted 2 January 2016)

ISSN 2167-8421 print/ISSN 2167-9223 online ß 2016 Taylor & Francis
DOI: 10.3109/21678421.2016.1143513
 2 F. Trojsi et al.

sophisticated psychometric approach, in consider- recruited had additional neurological disease or

ation of the few assessment resources currently
validated in Italian populations, we hypothesized
that different patterns of cognitive and behavioural
impairment would emerge in different King’s stages.
In particular, we aimed at underlining the limitation
of most existing tools that do not correct neuropsy-
chological scores for motor disability, especially in
advanced stages of disease.
previous mental illness.
The research was conducted according to the
principles expressed in the Declaration of Helsinki.
Ethics approval was obtained from the Ethics
Committee of Second University of Naples.
Patient or family written consent was obtained
from each participant.
Neuropsychological assessment

Materials and methods All participants underwent a 60-min neuropsycho-

logical battery, aiming to assess a broad range of
Patients cognitive skills, particularly those commonly
impaired in FTLD, according to ALS-FTD
Seventy-four (males 47%; mean age 60.3  11.2)
Consensus Criteria (17) (details about the Italian
right-handed and native Italian speakers patients, 46
versions of the adopted tests are provided in
with clinically definite and 28 with probable or
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Supplementary information). The neuropsycho-

probable laboratory-supported ALS, according to
diagnostic El Escorial criteria of ALS (14), were
consecutively recruited at the First Division of
Neurology of the Second University of Naples
(Naples, Italy) from 2013. Clinical parameters
were measured in all ALS patients by the ALS
functional rating scale-revised (ALSFRS-R) score,
index of disability status (15), and upper motor
neuron (UMN) score, a measure of pyramidal
dysfunction (16). All patients were classified accord-
ing to the King’s clinical staging system (13), based
on the appearance of sequential clinical milestones
during the ALS course. In particular, 16 patients
were classified in stage 1 (i.e. functional involvement
of one central nervous system region (symptom
onset); 20 in stage 2 (i.e. with involvement of two
regions); 17 patients in stage 3 (i.e. with involve-
ment of three regions); and 21 in stage 4 (specific-
ally, in the sub-stage 4B, needing non-invasive
ventilation) (for more details about the studied
population, see Table I). None of the patients
Table I. Demographic and clinical characteristics of the patients included in this study.
logical protocol used in this study allowed to
assess: 1) global cognitive impairment by
Addenbrooke’s Cognitive Examination Revised
(ACE-R) (18); 2) executive performances by
Frontal Assessment Battery (FAB), Stroop Colour-
Word Interference test and Trail Making Test,
considering the difference between part B and A
(TMT B-A) to remove the speed element from test
evaluation (19,20); 3) working, short-term and
long-term memory by forward and backwards digit
span tasks and memory prose test; 4) visuospatial
abilities by Raven’s Colour Progressive Matrices
(RCPM), that also explored current function and
Intelligence Quotient (IQ); 5) behavioural dysfunc-
tions by Frontal Systems Behaviour (FrSBe) Scale
(referring to the total scores at the time of examin-
ation, derived from the caregivers’ forms) (21); 6)
depressive symptoms by Beck Depression
Inventory-II (BDI-II). The tests were administered
following the same sequence for avoiding possible

ALS patients ALS patients ALS patients ALS patients in

with involvement with involvement with involvement non-invasive Between-groups
of a first region of a second region of a third region ventilation comparisons
Clinical features (stage 1) (n ¼ 16) (stage 2) (n ¼ 20) (stage 3) (n ¼ 17) (stage 4) (n ¼ 21) (p-values)
Age 59.9 (9.6) 58.7 (9.2) 56.4 (7.7) 58.1 (12.4) 0.787
Gender (males: females) 11:5 10:10 11:6 13:8 0.677
Education (years) 11.9 (3.9) 10.6 (2.7) 9.8 (2.6) 9.5 (2.6) 0.092
Disease duration (months) 31.6 (25.6) 53.5 (52.4) 54.4 (36.7) 58.8 (61.6) 0.244
El Escorial criteria (definite: probable) 10:6 10:10 9:8 17:4 0.17
Site of onset* 3:7:6 2:8:10 3:7:7 4:8:9 0.703
(bulbar: upper limbs: lower limbs)
IQ 102.3 (7.7) 92.8 (15.6) 91.1 (18.2) 86.5 (22.6) 0.078
BDI-II 10.1 (5.5) 12.7 (6.8) 11.1 (7.9) 12.7 (6.4) 0.611
ALSFRS-R 42.1 (3.1) 35.6 (4.5) 28.6 (7.5) 24.8 (5.1) 5.001
UMN score 4.3 (3.7) 6.5 (4.6) 7.2 (4.4) 7.9 (5.2) 0.008

The values displayed are mean (SD).

*With regard to characterization of clinical phenotypes, 56 patients exhibited a classic phenotype, six a bulbar phenotype, four a pyramidal
phenotype, two a flail arm phenotype and two a flail leg phenotype. Genetic analysis was performed in all patients, screening mutations of
SOD1, C9orf72 and TARDBP genes. Two patients, positive for abnormal hexanucleotide repeat expansions of C9orf72 gene with a
classic ALS phenotype (i.e. one in stage 2 and one in stage 3) and dysexecutive abnormalities (i.e. classified as ALS-ECI), were included
in the study.

interference of the answers of one test over the
others (8). Patients’ oxygen saturation was mea-
sured at the time of each examination using a pulse
oximetry: none of patients showed oxygen satur-
ation592 mmHg. If the subject was too tired during
testing, usually performed in the morning, a new
session was scheduled to complete the battery
within two weeks after the first one. In some cases,
initially collaborative patients declined to complete
the battery because of severe fatigue, causing
missing entries in the final data (see Table II for
the effective number of patients who executed each
test). Of note, the four groups of ALS patients who
performed all tests, including the timed tasks, were
matched for ALSFRS-R bulbar (i.e. items 1–3) and
fine/gross motor (i.e. items 4–9) subscores (15).
Patients unable to complete the battery were
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excluded from analyses, although such cases were
retained in the dataset, following Machts et al. (7).
Cognitive classification of patients was carried
out as follows, according to Montuschi et al. (8):
ALS with normal cognition (ALS-NC); ALS with
executive cognitive impairment (ALS-ECI) (i.e.
abnormal scores in two tests exploring the executive
domain); ALS with non-executive cognitive impair-
ment (ALS-NECI) (i.e. abnormal scores in two tests
exploring non-executive domains); ALS with
behavioural impairment (ALS-Bi) (i.e. predominant
behavioural disturbances with or without abnormal
scores in only one executive test); ALS with non-
classifiable cognitive impairment (ALS-NCCI) (i.e.
abnormal scores in one executive and/or one non-
executive domain with or without behavioural dys-
functions). We compared neuropsychological scores
in all patient groups to reference normative data (see
Supplementary information for more details on
Italian reference normative data adopted and Table
II for the number of patients who scored in the
pathological range). In one patient with suspect
comorbid bvFTD, a more comprehensive neuro-
psychological (including copy and delayed recall
trials of Rey-Osterrieth Complex Figure Test, spatial
span and Frontal Behavioural Inventory) and
neuroimaging (including 18F-2-fluoro-2-deoxy-D-
glucose positron emission tomography) evaluation
was performed, fulfilling the diagnostic criteria for
bvFTD (2).
Statistical analyses
Clinical, demographic and neuropsychological data
were tested for normality using the Kolmogorov-
Smirnov test, implemented in the Statistical toolbox
of Matlab v2012a (The Mathworks Inc., Natick,
MA, USA). The results of the test at a ¼ 0.05
indicated that neuropsychological scores were not
normally distributed. The demographic variables,
found to be normally distributed, were compared
among the four groups using one-way analysis of
variance (ANOVA). The categorical variables
Cognitive functioning in ALS stages 3
gender and site of onset were investigated using a
2 test. The neuropsychological performances were
compared among the four groups by using Kruskal-
Wallis test and, then, a post hoc analysis by Mann-
Whitney U-test was performed for all possible group
pairs. To reduce type I error associated with multiple
comparisons, a correction according to Bonferroni
criterion was applied to p-values (0.05/number of
cognitive variables). Additionally, given the low
number of patients per group, post hoc power
analysis was performed by using the G*Power
computer program (Faul & Erdfelder, Bonn
University, Germany) to evaluate the statistical
power for each group.
Results
Age, years of education, disease duration, gender,
BDI-II and IQ scores were not significantly different
among the four groups of ALS patients. In contrast,
ALSFRS-R and UMN scores showed more abnor-
mal scores in more advanced King’s stages of disease
(Table I). Patients’ classification according to cog-
nitive status is reported in Figure 1. The post hoc
power analyses for each stratified group revealed a
statistical power value of 0.58 for stage 1; 0.67 for
stage 2; 0.60 for stage 3; and 0.69 for stage 4.
Comparing the four groups of patients, after
Bonferroni correction (0.05/8 ¼ 0.006), Kruskal-
Wallis test showed significant differences on ACE-R
[2(3): 16.110, p ¼ 0.001], memory prose test
[2(3): 13.850, p ¼ 0.003], FAB [2(3): 19.433, p ¼
0.0001] and TMT B-A [2(3): 13.045, p ¼ 0.005].
Post hoc analysis, with Bonferroni correction
(i.e. 0.05/6 ¼ 0.008), showed that (Table II): 1) with
regard to general cognitive assessment (i.e. by ACE-
R), data collected in patients in stage 1 were
significantly different from those collected in
patients in stages 3 and 4; 2) with regard to
executive performances, data collected in patients
in stage 1 were significantly different from those
collected in patients in stage 2, 3 and 4 for FAB and
from those collected in patients in stages 3 and 4 for
TMT B-A; 3) with regard to long-term memory,
explored by memory prose, performances of
patients in stage 1 were significantly different from
those of patients in stages 3 and 4 (Table II).
Differently from results derived from evaluation
of executive and memory domains, investigation of
visuospatial abilities and neurobehavioural functions
did not show any significant between-groups differ-
ences in the comparison of the four King’s stages
(Table II).
Discussion
Our cross-sectional study reports the first evidence
that increasing cognitive deficits in ALS may be
associated with the progressive clinical milestones of
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Table II. Neuropsychological data evaluated in the four groups of ALS patients: raw scores are mean (SD) (first line). For each test, the total number of patients examined (n) and, in brackets, the number of
those who scored under reference normative data are reported (second line). Significant differences between all possible group pairs (post-hoc analysis) are shown in bold.
F. Trojsi et al.

1 vs. 2 1 vs. 3 1 vs. 4 2 vs. 3 2 vs. 4 3 vs. 4

Stage 1 Stage 2 Stage 3 Stage 4 U-test (p) U-test (p) U-test (p) U-test (p) U-test (p) U-test (p)
Global cognitive functions
ACE-R 90.2 (7.1) 85 (8.3) 74.9 (22.1) 71.7 (21.5) 84.5 38.0 36.0 130.5 115.0 135.5
n ¼ 14 (1) n ¼ 20 (1) n ¼ 17 (4) n ¼ 18 (5) (0.051) (0.001) (0.0001) (0.232) (0.035) (0.415)
Executive functions
Digit span backward 4.8 (0.8) 4.2 (1.1) 3.6 (1) 3.3 (1.7) - - - - - -
n ¼ 14 (1) n ¼ 20 (2) n ¼ 17 (3) n ¼ 18 (5)
Stroop test errors 0.2 (0.8) 3.1 (5.6) 2.2 (3.7) 2.7 (6) - - - - - -
n ¼ 14 (13) n ¼ 20 (19) n ¼ 17 (14) n ¼ 18 (18)
FAB 16.8 (1.5) 13.6 (3) 12.3 (2.8) 11.6 (4.5) 33.0 12.0 26.0 76.5 78.0 78.0
n ¼ 14 (5) n ¼ 16 (16) n ¼ 13 (13) n ¼ 13 (11) (0.001) (5.001) (0.001) (0.232) (0.268) (0.762)
TMT B-A 86.5 (35.3) 217.7 (171.1) 246.4 (178.5) 296.2 (162.5) 41.5 18.5 36.5 121.5 136.5 171.0
n ¼ 14 (0) n ¼ 20 (8) n ¼ 17 (10) n ¼ 18 (6) (0.062) (0.004) (0.001) (0.208) (0.088) (0.839)
Memory
Memory prose 12.9 (3.5) 10.4 (3.8) 9.4 (2.2) 8.5 (3.3) 82.5 41.0 45.5 140.0 116.5 112.5
n ¼ 14 (1) n ¼ 20 (1) n ¼ 17 (3) n ¼ 18 (4) (0.043) (0.001) (0.002) (0.373) (0.063) (0.184)
Digit span forward 6 (1.51) 4.9 (1.8) 4.5 (1) 4.3 (1.7) - - - - - -
n ¼ 14 (3) n ¼ 20 (9) n ¼ 17 (9) n ¼ 18 (8)
Visuospatial and general functions
RCPM 27.6 (2.7) 24.5 (5.5) 24.1 (6.2) 22.7 (6.2) - - - - - -
n ¼ 16 (0) n ¼ 20 (4) n ¼ 17 (4) n ¼ 21 (5)
Neurobehavioural functions
FrSBe total score 82.6 (14.4) 95.7 (23.6) 93.4 (23.2) 107.5 (24.9) - - - - - -
n ¼ 16 n ¼ 20 n ¼ 17 n ¼ 21

ACE: Addenbrooke’s Cognitive Examination-Revised; FAB: Frontal Assessment Battery; FrSBe: Frontal Systems Behaviour; RCPM: Raven’s Colored Progressive Matrices.

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Figure 1. Patients’ classification according to cognitive status: percentages of the different cognitive profiles in the four King’s stages of
ALS. ALS-Bi: ALS with behavioural impairment; ALS-ECI: ALS with executive cognitive impairment; ALS-NC: ALS with normal
cognition; ALS-NCCI: ALS with non-classifiable cognitive impairment; ALS-NECI: ALS with non-executive cognitive impairment;
bvFTD: behavioural variant FTD.
disease, as defined according to the King’s clinical
staging system (13). Specifically, in all King’s stages
examined, we separated cognitive profiles of ALS
patients by type and explored the main cognitive
domains for possible different neuropsychological
and behavioural patterns. We found that cognitive
impairment was primarily related to frontotemporal
degeneration in all King’s stages, with poorer
performances in clinical phenotypes characterized
by a wider disability. However, the limits of current
standard assessment procedures, that are not able to
account for physical disability during disease course,
are also to be discussed.
Our results are in line with previous cross-
sectional (4–8) and longitudinal (9–12) studies as
we confirm a prominent decline of executive and
language performances in ALS patients, which is
more strikingly in bulbar (8) and pseudobulbar (4)
phenotypes. However, we were not able to verify in
which measure different regions of disease onset
may be associated with different cognitive profiles in
the four groups of patients, due to the fact that
patients with bulbar onset were less numerous than
those with spinal onset (Table I). Moreover, in the
absence of longitudinal data, we were not able to
confirm previous longitudinal results that identified
a progressive impairment of cognitive domains
attributed to frontal and temporal lobes (9–12),
especially in patients with bulbar onset. In particu-
lar, Schreiber et al. (10) showed that cognitive
deficits did not progress in synchrony with motor
Cognitive functioning in ALS stages 5
decline, but more slowly, although patients with
bulbar-onset ALS had a relatively greater cognitive
impairment over time than subjects with spinal-
onset phenotypes. More recently, Elamin et al. (11)
showed that evidence of executive dysfunctions at
the ALS onset may be associated with significantly
faster motor decline, particularly in the bulbar sites.
Against this background, the results of our cross-
sectional analysis more clearly suggest that cognitive
impairment, especially when involving executive
functions, could be observed upon presentation of
the early milestones of disease and could increase
with involvement of more body sites. However,
Lakerveld et al. (22) did not show any significant
cognitive alteration in a small cohort of patients with
late stage ALS, although in this study the ‘severely
physically impaired’ status corresponded to at least
15–30 months since diagnosis or first symptoms of
disease and presence of tetraparesis/tetraplegia.
Among the cognitive tests administered, in our
sample the ACE-R battery (18) allowed to ade-
quately differentiate the four King’s stages exam-
ined, detecting more impaired global performances
in the highest ones. However, the reliability of this
finding may be questioned by the fact that the ACE-
R battery has some intrinsic limitations in the
examination of ALS patients. Although ACE-R
has been shown to be useful for standard screening
of dementia by health care professionals within the
clinic, in ALS patients with severe physical disability
(i.e. affecting bulbar site or upper limbs or both),
 6 F. Trojsi et al.
this battery could magnify decrements in cognitive
performances, due to physical obstacles experienced
by these patients in the performance of some items
(1). In this regard, our analysis did not allow to
assess how and in which measure ACE-R may
account for cognitive impairment in the presence of
motor disability in different stages of ALS.
Furthermore, the choice of this non-ALS-specific
tool was determined by the current lack of other
validated batteries for multi-domain cognitive
assessment. A more appropriate tool for cognitive
screening in both research and clinical settings
might be represented by the Edinburgh Cognitive
and Behavioural ALS Screen (ECAS) battery (24),
although it is not still validated in populations other
than English and German ones (25,26), thus limit-
ing, at present, its implementation worldwide.
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Assessment of executive functions in our popu-
lation confirmed previous evidence from clinic- and
population-based studies revealing that mainly
executive performances are impaired already
during early stages of ALS (8,11,12). In particular,
our between-group comparisons showed that FAB
and TMT B-A allowed to distinguish subsets of less
disabled patients (i.e. in stage 1) from more disabled
ones (i.e. in stages 3 and 4). However, the general
validity of these results is substantially reduced by
the sample bias introduced by the limited number of
patients who agreed to perform the tests (see Table
II). Despite this limit, our data seem to corroborate
previous histochemical (26) and neuroimaging
(27,28) evidence on prominent frontal dysfunction
described in different phenotypes of ALS. With
regard to the application of FAB for assessing
executive dysfunctions in ALS, our data unravelled
poor performances already at the initial stages, with
increasing decline during ALS progression, and
therefore seem to support the possible use of this
cognitive battery as an early testing tool. Previous
evidence revealed that, from disease onset, FAB may
be helpful to identify ALS patients who need further
neuropsychological investigation (29). However, in
this test, the effect of bulbar and motor (dominant-
arm) dysfunctions may hinder patients in carrying
out all the requested tasks. To limit the ALS-related
speed effects on executive function assessment, it
may be more informative to compute the difference
or the ratio between part B and A of TMT (7,19,20)
and, possibly, more convenient to evaluate ‘fluency
indices’ after correction of spoken or written verbal
fluency scores for speed of response (30). In this
regard, another important limitation of our study is
the lack of fluency indices, due to the fact that only
TMT B-A scores between the four groups of
patients could be calculated.
The investigation of non-executive domains in
our population revealed that patients’ performances
at memory prose test were significantly different
when comparing the four groups of patients, and the
earlier versus the more advanced King’s stages of
disease, thus corroborating previous findings that
memory functions may also be increasingly affected
in the ALS course, albeit only to some extent in the
context of comorbid executive dysfunctions, which
may significantly impact recognition and, then,
encoding abilities (31). This is also supported in
our population by the coexisting abnormalities of
both FAB and memory prose test when comparing
one to three or four groups (7,32).
Alteration of visuospatial abilities and behav-
ioural and depressive symptoms was not signifi-
cantly different when comparing the four subsets of
patients. In this regard, there is growing evidence
that visuospatial abilities are less impaired than
language and executive functions in ALS patients
(8), similarly to what was frequently described in
patients affected by FTLD (1). Conversely, neuro-
behavioural dysfunctions, that mainly consist of
apathy, dysexecutive behaviours and disinhibition,
and have been linked to frontal impairment (33),
have been observed in a substantial proportion of
ALS patients. This has probably affected the
acceptance of (and compliance to) life-prolonging
therapies (34). In particular, for what concerns
mood disturbances in ALS, several studies are not in
favour of a potential association between depression
and motor (6) or cognitive/behavioural (33) symp-
toms in ALS. However, more recently, Jones et al.
(35), who evaluated health utility and emotional
status, including depression and anxiety, in a popu-
lation of 214 ALS patients classified according to
King’s staging system, showed that both measures
worsened as ALS progressed. Probably, the dissimi-
larity between these results and ours about mood
changes across ALS course may be due to the
different clinical measures used in the two studies
(i.e. Hospital Anxiety and Depression Scale,
adopted in the English population, versus BDI-II
scale, used in our assessment) and the larger
number and multi-centre affiliation of the subjects
examined by Jones et al.
Limitations of our study pertain to the relatively
small size of each subset of patients, the mono-
centric affiliation of the population, and the cross-
sectional design of the work. We should also
acknowledge the low statistical power of each
stratified group. Moreover, clinic-based characteris-
tic of the studied sample limits the validity of our
results to the general ALS population. Other limi-
tations are linked to the neuropsychological protocol
used, given that some ALS-specific tools were not
used because still not available in validated Italian
versions (23,36), and to the intrinsic heterogeneity
of clinical phenotype within the same ALS subgroup
that could have increased the variability of cognitive
performance in some tests.
In summary, we observed that cognitive impair-
ment may develop early in the ALS course with
prominent involvement of executive and memory
functions across the four King’s stages of disease.

Neuropsychological information could further sup-
plement the clinical characterization of patients,
integrating the current system of disability evalu-
ation. However, validation on large populations
worldwide and implementation in clinical practice
of ALS-specific multi-domain screening instruments
would be auspicious for adequately exploring both
cognitive and behavioural dysfunctions also in
advanced stages of disease.
Declaration of interest
The authors disclosure no conflict of interest.
Outside this work, F. Trojsi received fees from
Italfarmaco and grants from Novartis, G. Caiazzo
grants from Sanofi, M. Monsurrò grants from
AISLA and G. Tedeschi fees from Biogen and
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MerckSerono and grants from AISLA.
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Italian versions of the neuropsychological tests used are available

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http://dx.doi.org/10.3109/21678421.2016.1143513.